Atherosclerotic cardiovascular disease is the leading cause of death and disability in the world, accounting for nearly one-third of all human mortality. Over the past fifty years, significant progress has been made in the understanding and primary prevention of atherosclerosis. Still, as patients age and their arteries become brittle and elongated, early atherosclerotic plaques inexorably progress to their occlusive end-stage and induce the clinical syndromes of angina pectoris (chest pain), transient ischemic attack (reduced blood flow to the heart) and claudication (leg pain due to poor circulation) and their sinister end-stages of myocardial infarction (“heart attack”), stroke and amputation.
In the modern era, the mainstay of therapy for established vascular lesions is percutaneous balloon angioplasty (dilating the constricted artery with a balloon catheter) and stent implantation. The procedure is widely used, over 2,000,000 procedures performed annually, and the short-term results are favorable in >95% of patients. Significant problems with angioplasty and stenting remain, however, including the requirement for continued antiplatelet medication as the artery heals, the frequent need for early re-intervention for restenosis (when the stented artery closes down again), and thrombosis (clot formation). Furthermore, although there has been remarkable progress in intravascular stent development, stents still generate an alarming number of long-term complications, including fracture and late thrombosis.
In order to circumvent the myriad problems associated with permanent metal implants, stents that slowly dissolve after deployment have long been imagined and researched. Due to their temporary nature, such devices are also known as “scaffolds” rather than “stents” which remain in the body permanently. Bioresorbable vascular scaffolds (BVS or “bioresorbable stents”) potentially offer several key biologic and physiologic advantages, including: (1) effective scaffolding without the permanence of a metal implant; (2) attenuation of chronic inflammation and foreign body reaction; (3) promotion of adaptive vascular remodeling; (4) restoration of physiologic vasoactive function; and (5) facilitation of imaging and surveillance during follow-up. Despite their promise, however, the devices have proven challenging to successfully design, develop and manufacture. At the current time, only two coronary devices and a single peripheral device are available commercially in Europe, and no devices have yet been approved for use in the United States.
A key limitation of intravascular stents is their inability to conform to and accommodate the natural bending and twisting of blood vessels during human movement. This is particularly problematic in the blood vessels of the extremities, which bend and twist in unpredictable fashion, depending on the type, degree and rapidity of human motion. For instance, Cheng et al. quantified in vivo arterial deformation using magnetic resonance angiography and found that, during movement from the supine to the fetal position, the superficial femoral artery (SFA) shortened an average of 13% and twisted an average of 60°. A subsequent study in elderly subjects found lesser degrees of shortening with flexion, but substantially more curvature and buckling. Other studies have had similarly dramatic results.
The motion and deformation of stents implanted in actual human SFAs has also been studied. For instance, Nikanorov et al. deployed eleven 100 mm self-expanding nitinol stents in the femoropopliteal arteries of eight cadavers and assessed length and deflection via lateral view radiographs obtained during simulated flexion. The results showed that stents implanted in the SFA and popliteal arteries exhibited compression of up to 10.7%, depending on the degree of flexion. More notably, stents implanted in the mid-popliteal artery bent an average of 54° when the leg was fully flexed.
Stents implanted in short, motionless arteries are typically rigid and non-deformable. So-called “balloon-expandable” stents are deployed by inflating their delivery balloon within the target lesion and embedding the rigid scaffold within the vessel wall. The final stent shape is fixed, casted and restrained by the contour of its surrounding vessel. Its architecture is permanent; reimaging the device over time generally reveals no change in the diameter that was achieved during the procedure.
In contrast, the length and motion of the long extremity vessels mandates that stents designed for this anatomic location have the properties of flexibility and conformability. Most devices designed for the extremities are made of a nickel-titanium alloy known as “Nitinol” which has intrinsic properties of super-elasticity and shape memory. Nitinol stents are “self-expanding”, they are deployed by progressively releasing the device from a long tube in which it is housed. The delivery system does not contain a balloon (although the device is routinely “post-dilated” with a balloon that is separately inserted). Unlike balloon-expandable stents, self-expanding Nitinol stents are neither rigid nor fixed. Their flexibility allows them to the recover when deformed, a critical property for a long device implanted into an extremity artery. In this respect, Nitinol stents resemble bypass grafts: flexible, long conduits that carry blood past obstructive lesions.
However, the necessity for flexibility and conformability in peripheral vascular stents means that these stents have historically had far less radial strength than typical balloon expandable stents. In this regard, such flexible, conformable stents do little to actually “stent” (or “prop open”) the artery; unconstrained by a scaffold, the artery is free to collapse over time. Furthermore, stents designed in this manner must be “oversized,” to remain in place and continue to exert a “chronic outward force” upon the vessel until such time that the nominal diameter of the device is reached. Some have theorized that the chronic force imparts continuous injury to the artery, resulting in poor long-term patency. Thus, the design of an effective, self-expanding, flexible stent is fundamentally different from traditional, rigid, “balloon-expandable” metal stents, which exert a singular “stretch” at the time of implantation and then remain inert as the vessel recovers and remodels.
The length and persistent motion of the extremity arteries also lead to a tendency toward fracture of stents implanted in those arteries. Stent fracture following femoropopliteal implantation is alarmingly common. Movement of the legs is a complex motion; loading of the hips and knees during ambulation repeatedly compresses the arteries axially and can even produce multidimensional bends, twists and kinks. This results in single or multiple strut fractures or, in severe cases, complete stent transection. Fracture is more common after implantation of long and/or overlapping stents and, possibly, in more active patients. Fracture of intravascular stents is clearly associated with restenosis.
Therefore, it would be advantageous to have a bioresorbable stent for use in peripheral vasculature that is easier to design, develop and manufacture than currently available stents. Ideally, such a stent would have a desirable flexibility and conformability profile while also having sufficient strength to withstand the stresses placed on peripheral vascular stents, as described above. This would make the stent more useful and effective, and safe for the treatment of long, tortuous blood vessels. Ideally, such a stent would also provide at least some of the advantages of absorbable (or “bioresorbable”) stents listed above. At least some of these objectives will be met by the embodiments described below.